Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 64, Issue 22, Pages 16512-16529Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.1c01078
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Funding
- Italian MIUR/PRIN 2017 [2017FJZZRC]
- European Research Council (ERC) [101001784]
- Swiss National Supercomputing Center (CSCS) [u8]
- European Research Council (ERC) [101001784] Funding Source: European Research Council (ERC)
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GPCRs are important molecular targets for drug development, with potential for multitarget drugs. Compounds with dual activity towards CysLT(1)R and GPBAR1 show promise in treating inflammatory diseases such as colitis. The binding mode of these compounds reveals structural basis for future drug design studies.
G-protein-coupled receptors (GPCRs) are the molecular target of 40% of marketed drugs and the most investigated structures to develop novel therapeutics. Different members of the GPCRs superfamily can modulate the same cellular process acting on diverse pathways, thus representing an attractive opportunity to achieve multitarget drugs with synergic pharmacological effects. Here, we present a series of compounds with dual activity toward cysteinyl leukotriene receptor 1 (CysLT(1)R) and G-protein-coupled bile acid receptor 1 (GPBAR1). They are derivatives of REV5901-the first reported dual compound-with therapeutic potential in the treatment of colitis and other inflammatory processes. We report the binding mode of the most active compounds in the two GPCRs, revealing unprecedented structural basis for future drug design studies, including the presence of a polar group opportunely spaced from an aromatic ring in the ligand to interact with Arg79(2.60) of CysLT(1)R and achieve dual activity.
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